Among excitatory amino acid receptor antagonists recognized for usefulness in the treatment of disorders are those that block N-methyl-D-aspartate (NMDA) receptors.
For example, heterocycles containing nitrogen, and having phosphonic acid and carboxylate substituents, are found in European Application Publication Nos. 0159889 and 0203891 which disclose utility for the treatment of nervous system disorders. The disorders disclosed which are responsive to blockade of the NMDA receptor include cerebral ischaemia, muscular spasms (spasticity), convulsive disorders (epilepsy), and anxiety. These compounds, however, are readily distinguished from the compounds of the present invention both by the nitrogen containing heterocycles and by the various substituents thereon.
Aliphatic .alpha.-amino acids are disclosed in British Patent Nos. 2,104,078 and 2,156,818. The first of these, No. 2,104,078, includes 2-amino-7-phosphonoheptanoic acid (APH) disclosed for use in treating Huntington's disease, Alzheimer's disease, and certain forms of epilepsy as well as for use in the prevention of brain damage associated with stroke (see SCRIP #1067, Jan. 13, 1986, page 22). The second of these, 2,156,818, discloses usefulness for treating epilepsy, disorders associated with excess growth hormone (GH) or luteinizing hormone (LH) secretion, schizophrenia, depression, CNS degenerative disorders, and cerebral hypoxic conditions.
More particularly, U.S. Pat. No. 4,657,899 discloses compounds of the formula ##STR1## wherein n and m=0, 1, 2, or 3 and X.sup.1 and X.sup.2 are the same or different and are selected from the group consisting of hydrogen, lower alkyl, halogen, --CH.dbd.CH--CH.dbd.CH--, amino, nitro, trifluoromethyl, or cyano, having activity as anticovulsants, analgesics, and cognition enhancers through the antagonism of specific excitatory amino acid neurotransmitter receptors.
The novel substituted .alpha.-amino acids of the present invention are not made obvious by these disclosures. In fact, clearly the disclosure of U.S. Pat. No. 4,657,899 is limited to a specific ortho positioning of phosphonic acid and amino acid residues on a phenyl ring. Such a limitation teaches away from the novel compounds of the present invention.
An understanding of the role of excitatory amino acids is expanded by J. C. Walkins, et al. in "Recent Advances in the Pharmacology of Excitatory Amino Acids" pp. 19-26 in Excitatory Amino Acid Transmission: Neurology and Neurobiology, Volume 24, Ed. by Hicks, Lodge and McLennan, Publisheer: Alan R. Liss, Inc., New York, 1987.
An additional reference is now found to compounds, for example, for the treatment of diseases responding to a blockade of NMDA-sensitive receptors, in European Application Publication No. 0233154, of the formula ##STR2## showing a basic difference in that the phosphorus containing substituent and the amino/carboxy containing substituent are linked through a straight chain double bonded C.dbd.C linkage and not as substituents on a common aryl ring.
Then, on the other hand antagonists to the NMDA sensitive excitatory amino acid receptors are shown in U.S. Pat. No. 4,746,653, filed Feb. 28, 1986 to include substituted saturated pyridinyl ring systems common to both a phosphorus containing and carboxy or carboxy derivatized substituent.
More recently, the British Patent Application No. 15 2,198,134 filed Oct. 30, 1986 but not published before Jun. 8, 1988 teaches compounds useful for treating epilepsy including anticonvulsant activity shown from inhibition of NMDA in excitatory amino acid systems having the formula ##STR3## wherein R.sub.1 is a carboxy or carboxy containing analogue and y is a ##STR4## containing substituent. However, the present invention is defined by a scope not taught within the broad disclosure of this application and, therefore, represents an advance not made obvious therein.
Although a related reference teaches "The Synthesis of p-Substituted D,L-Phenylglycines by the Amidoalkylation of
Benzylchloride and N-Benzylbenzamide, Tetrahedron, Vol. 33, pp. 2715-7 (1977) by D. Ben-Ishai et al, it does not make obvious the use of the process for phosphonate containing derivatives.